Centers for Medicare and Medicaid Services

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1 Centers for Medicare and Medicaid Services Clinical Laboratory Fee Schedule Annual Laboratory Public Meeting June 25, 2018 Anthony Sireci, MD, Msc Association for Molecular Pathology

2 Outline Germline Procedures o Triplet Repeat Disorders Procedures - Evaluation of abnormal alleles (8X001, 8X003, 8X006-8X013, 8X016, 8X017, 8X020, 8X022, 8X026, 8X028, 8X035, 8X036) o Triplet Repeat Disorders Procedures - Characterization of alleles (8X002, 8X021, 8X023, 8X027) o Full Gene Sequence Procedures (non-brca) (8X004, 8X014, 8X018, 8X024, 8X033) o Familial Variant Detection Procedures (non-brca) (8X005, 8X015, 8X019, 8X025, 8X034) o Common Variant Detection Procedures (non-brca) (8X000, 813X0, 8X032) o BRCA Procedures (81X78, 81X79, 81X81, 81X82, 81X83) Oncology-related Procedures o Common Variants or Targeted Sequencing Procedures (81X08-81X11, 80X00) o Full Gene Sequence Procedures (81X07) Genomic Sequencing Procedure (81X43) Reconsidered Procedures (81334 and 81326)

3 Basis for Crosswalk Recommendations Analysis of: Analytical methods employed Overall resources utilized Types of genetic variants tested (e.g., SNPs, deletions, etc.,.) Amount of genetic material interrogated

4 Background: Triplet Repeat Disorders Evaluation of Abnormal Alleles 8X001, 8X003, 8X006-8X013, 8X016, 8X017, 8X020, 8X022, 8X026, 8X028, 8X035, 8X036 New Code Descriptor 8X001 AFF2 (AF4/FMR2 family, member 2 [FMR2]) (eg, fragile X mental retardation 2 [FRAXE]) gene analysis; evaluation to detect abnormal (eg, expanded) alleles 8X003 AR (androgen receptor) (eg, spinal and bulbar muscular atrophy, Kennedy disease, X chromosome inactivation) gene analysis; characterization of alleles (eg, expanded size or methylation status) 8X006 8X007 8X008 8X009 ATN1 (atrophin 1) (eg, dentatorubral-pallidoluysian atrophy) gene analysis, evaluation to detect abnormal (eg, expanded) alleles ATXN1 (ataxin 1) (eg, spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (eg, expanded) alleles ATXN10 (ataxin 10) (eg, spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (eg, expanded) alleles ATXN2 (ataxin 2) (eg, spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (eg, expanded) alleles 8X010 8X011 8X012 8X013 8X016 8X017 8X020 8X022 8X026 8X028 8X035 8X036 ATXN3 (ataxin 3) (eg, spinocerebellar ataxia, Machado-Joseph disease) gene analysis, evaluation to detect abnormal (eg, expanded) alleles ATXN7 (ataxin 7) (eg, spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (eg, expanded) alleles ATXN8OS (ATXN8 opposite strand [non-protein coding]) (eg, spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (eg, expanded) alleles CACNA1A (calcium voltage-gated channel subunit alpha1 A) (eg, spinocerebellar ataxia) gene analysis; evaluation to detect abnormal (eg, expanded) alleles CNBP (CCHC-type zinc finger nucleic acid binding protein) (eg, myotonic dystrophy type 2) gene analysis, evaluation to detect abnormal (eg, expanded) alleles CSTB (cystatin B) (eg, Unverricht-Lundborg disease) gene analysis; evaluation to detect abnormal (eg, expanded) alleles DMPK (DM1 protein kinase) (eg, myotonic dystrophy type 1) gene analysis; evaluation to detect abnormal (expanded) alleles FXN (frataxin) (eg, Friedreich ataxia) gene analysis; evaluation to detect abnormal (expanded) alleles HTT (huntingtin) (eg, Huntington disease) gene analysis; evaluation to detect abnormal (eg, expanded) alleles PABPN1 (poly[a] binding protein nuclear 1) (eg, oculopharyngeal muscular dystrophy) gene analysis, evaluation to detect abnormal (eg, expanded) alleles PPP2R2B (protein phosphatase 2 regulatory subunit Bbeta) (eg, spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (eg, expanded) alleles TBP (TATA box binding protein) (eg, spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (eg, expanded) alleles

5 Test Purpose and Method: Triplet Repeat Disorders- Procedures Evaluation of Abnormal Alleles 8X001, 8X003, 8X006-8X013, 8X016, 8X017, 8X020, 8X022, 8X026, 8X028, 8X035, 8X036 Purpose: To aid in the diagnosis of a triplet repeat disorder. Method: Repeat primed PCR with capillary electrophoresis

6 Crosswalk Recommendations: Triplet Repeat Disorders Procedures Evaluation of Abnormal Alleles - 8X001, 8X003, 8X006-8X013, 8X016, 8X017, 8X020, 8X022, 8X026, 8X028, 8X035, 8X036 New Code Gene Name Public Comment Rationale 8X001 AFF2 8X003 AR 8X006 ATN1 8X007 ATXN1 8X008 ATXN10 8X009 ATXN2 8X010 8X011 8X012 8X013 8X016 8X017 8X020 8X022 8X026 8X028 8X035 8X036 ATXN3 ATXN7 ATXN8OS CACNA1A CNBP CSTB DMPK FXN HTT PABPN1 PPP2R2B TBP Molecular Pathology Procedure Level 2 ($137.00) The methodology and amount of work used to detect triplet repeat expansion disorders is identical to that described by the Tier 2, level 2 code (81401), which is how these procedures were originally coded. 6

7 Background: Triplet Repeat Disorders Characterization of Alleles 8X002, 8X021, 8X023, 8X027 New Code Descriptor 8X002 8X021 8X023 AFF2 (AF4/FMR2 family, member 2 [FMR2]) (eg, fragile X mental retardation 2 [FRAXE]) gene analysis; characterization of alleles (eg, expanded size and methylation status) DMPK (DM1 protein kinase) (eg, myotonic dystrophy type 1) gene analysis; characterization of alleles (eg, expanded size) FXN (frataxin) (eg, Friedreich ataxia) gene analysis; characterization of alleles (eg, expanded size) 8X027 HTT (huntingtin) (eg, Huntington disease) gene analysis; characterization of alleles (eg, expanded size)

8 Test Purpose and Method: Triplet Repeat Disorders Procedures Characterization of Alleles 8X002, 8X021, 8X023, 8X027 Purpose: To aid in the diagnosis of a triplet repeat disorder. Method: Southern Blot

9 Crosswalk Recommendations: Triplet Repeat Disorders Procedures Characterization of Alleles 8X002, 8X021, 8X023, 8X027 Purpose: To aide in the diagnosis of a triplet repeat disorder. New Code Gene Name Public Comment Rationale 8X002 8X021 8X023 8X027 AFF2 Method: Southern Blot DMPK FXN HTT Molecular Pathology Procedure, Level 5 ($ ) The methodology and amount of work used to characterize the size of the triplet repeat expansion is identical to that described by the Tier 2, Level 5 code, which is how these procedures were previously coded.

10 Background: Germline Full Gene Sequence Procedures (non-brca) 8X004, 8X014, 8X018, 8X024, 8X033) New Code Descriptor 8X004 AR (androgen receptor) (eg, spinal and bulbar muscular atrophy, Kennedy disease, X chromosome inactivation) gene analysis; full gene sequence 8X014 CACNA1A (calcium voltage-gated channel subunit alpha1 A) (eg, spinocerebellar ataxia) gene analysis; full gene sequence 8X018 8X024 8X033 CSTB (cystatin B) (eg, Unverricht-Lundborg disease) gene analysis; full gene sequence FXN (frataxin) (eg, Friedreich ataxia) gene analysis; full gene sequence SMN1 (survival of motor neuron 1, telomeric) (eg, spinal muscular atrophy) gene analysis; full gene sequence

11 Test Purpose and Method: Germline Full Gene Sequence Procedures (non-brca) 8X004, 8X014, 8X018, 8X024, 8X033) Purpose: To detect variants (e.g., SNVs, indels) within the entire gene. Method: Bi-directional sequencing of coding regions as well as exon-intron junctions by Sanger sequencing or next generation sequencing.

12 Crosswalk Recommendations: Germline Full Gene Sequence Procedures (non- BRCA) 8X004, 8X014, 8X018, 8X024, 8X033 New Code Gene Name Public Comment Rationale 8X004 8X014 AR CACNA1A Methods used for sequencing analysis and the amount of DNA Molecular Pathology Procedure, sequenced are comparable to that of 81405, which is how this Level 6 ($301.35) procedure was previously coded Molecular Pathology Procedure, Level 8 ($846.27) Methods used for sequencing analysis and the amount of DNA sequenced are comparable to that of 81407, which is how this procedure was previously coded. 8X018 CSTB Molecular Pathology Procedure, Methods used for sequencing analysis and the amount of DNA Level 5 ($274.83) sequenced are comparable to that of 81404, which is how this procedure was previously coded. 8X024 FXN Molecular Pathology Procedure, Methods used for sequencing analysis and the amount of DNA Level 5 ($274.83) sequenced are comparable to that of 81404, which is how this procedure was previously coded. 8X033 SMN PMS2 (postmeiotic segregation increased 2 [S. cerevisiae]) (eg, hereditary non-polyposis colorectal cancer, Lynch syndrome) gene analysis; full sequence analysis ($707.02) Similar methodologies and resources are used in the full sequencing of SMN1 and PMS2.

13 Background: Germline Familial Variant Detection Procedures (non-brca) 8X005, 8X015, 8X019, 8X025, 8X034 New Code Descriptor 8X005 AR (androgen receptor) (eg, spinal and bulbar muscular atrophy, Kennedy disease, X chromosome inactivation) gene analysis; known familial variant 8X015 CACNA1A (calcium voltage-gated channel subunit alpha1 A) (eg, spinocerebellar ataxia) gene analysis; known familial variant 8X019 8X025 8X034 CSTB (cystatin B) (eg, Unverricht-Lundborg disease) gene analysis; known familial variant(s) FXN (frataxin) (eg, Friedreich ataxia) gene analysis; known familial variant(s) SMN1 (survival of motor neuron 1, telomeric) (eg, spinal muscular atrophy) gene analysis; known familial sequence variant(s)

14 Test Purpose and Method: Germline Familial Variant Detection Procedures (non-brca) 8X005, 8X015, 8X019, 8X025, 8X034 Purpose: To detect specific known variant(s) in a gene. Method: PCR amplification followed by a targeted genotyping method (e.g., Sanger Sequencing)

15 Crosswalk Recommendations: Germline Familial Variant Detection Procedures (non-brca) 8X005, 8X015, 8X019, 8X025, 8X034 New Code Gene Name Public Comment Rationale 8X005 AR 8X015 CACNA1A 8X019 8X025 CSTB FXN Molecular Pathology Procedure, Level 4 ($185.20) Methods used for sequencing analysis and the amount of DNA sequenced are comparable to that of 81403, which is how this procedure was previously coded. 8X034 SMN1

16 Background, Test Purpose and Method: Germline Common Variant Detection Procedures (non-brca) 8X000, 813X0, 8X032 New Code Descriptor 8X X0 NUDT15 (nudix hydrolase 15) (eg, drug metabolism) gene analysis, common variant(s) (eg, *2, *3, *4, *5, *6) TGFBI (transforming growth factor beta-induced) (eg, corneal dystrophy) gene analysis, common variants (eg, R124H, R124C, R124L, R555W, R555Q) 8X032 SMN1 (survival of motor neuron 1, telomeric) (eg, spinal muscular atrophy) gene analysis; dosage/deletion analysis, includes SMN2 (survival of motor neuron 2, centromeric) analysis, if performed Purpose: To detect specific, common variant(s) in a gene. Method: 8X000 and 812X0: PCR amplification followed by a targeted genotyping method (e.g., Sanger Sequencing) 8X032: Multiplexed Ligation-dependent Probe Amplification (MLPA) or delta delta CT

17 Crosswalk Recommendation: Germline Common Variant Detection Procedures (non-brca) 8X000, 813X0, 8X032 New Code 8X000 Gene Name Public Comment Rationale NUDT CYP2C19 (cytochrome P450, family 2, subfamily C, polypeptide 19) (eg, drug metabolism), gene analysis, common variants (eg, *2, *3, *4, *8, *17) ($291.36) Similar methodologies and resources are used to detect a comparable number of known variants in X0 TGFBI CYP3A4 (cytochrome P450 family 3 subfamily A member 4) (eg, drug metabolism), gene analysis, common variant(s) (eg, *2, *22) ($174.81) Similar methodologies and resources are used to detect a comparable number of known variants in X032 SMN1/ Molecular Pathology Procedures, Level 2 ($137.00) The methodology and amount of work used is identical to that described by the Tier 2, level 2 code which is how this procedure was previously coded

18 Background: BRCA Procedures 81X78, 81X79, 81X81, 81X82, 81X83 New Code Descriptor BRCA1 (BRCA1, DNA repair associated), BRCA2 (BRCA2, DNA repair associated) (eg, hereditary breast 81X78 and ovarian cancer) gene analysis; full sequence analysis 81X79 BRCA1 (BRCA1, DNA repair associated), BRCA2 (BRCA2, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; full duplication/deletion analysis (ie, detection of large gene rearrangements) 81X81 81X82 81X83 BRCA1 (BRCA1, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; full sequence analysis BRCA1 (BRCA1, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; full duplication/deletion analysis (ie, detection of large gene rearrangements) BRCA2 (BRCA2, DNA repair associated) (eg, hereditary breast and ovarian cancer) gene analysis; full duplication/deletion analysis (ie, detection of large gene rearrangements)

19 Test Purpose and Method: BRCA Procedures 81X78, 81X79, 81X81, 81X82, 81X83 Purpose: To detect variants (e.g., SNVs and small indels) within one or both BRCA genes in their entirety Method: Full gene sequencing: Bi-directional sequencing of coding regions as well as exon-intron junctions by Sanger sequencing or next generation sequencing Del/Dup analysis: Generally Multiplexed Ligation-dependent Probe Amplification (MLPA)

20 Crosswalk Recommendations: BRCA Procedures 81X78, 81X79, 81X81, 81X82, 81X83 New Code Gene Name Public Comment Rationale 81X78 81X79 BRCA1, BRCA2 full sequence analysis BRCA1, BRCA2 full duplication/deletion analysis DMD (dystrophin) (eg, Duchenne/Becker The methodology and amount of DNA sequenced is muscular dystrophy), full gene sequence; Molecular comparable to the sequencing of the large gene DMD. Pathology Procedure, Level 9 ($2,000.00) BRCA1, BRCA2 (breast cancer 1 and 2) (eg, hereditary breast and ovarian cancer) gene analysis; uncommon duplication/deletion variants ($553.00) The methodology used for detection of Dup/Dels is the same as the previously used code for BRCA1/2 Dup/del uncommon analysis. 81X81 81X82 81X83 BRCA1 full sequence analysis BRCA1 full duplication/deletion analysis BRCA2 full duplication/deletion analysis x0.5 ($2, X 0.5 = $1,000.00) The methodology and amount of DNA sequenced is comparable to half that of the sequencing of the large gene DMD x0.5 ($ X0.5= $276.5) The methodology used for detection of Dup/Del analysis is half that as the previously used code for BRCA1/2 Dup/del uncommon analysis x0.5 ($ X0.5= $276.5) The methodology used for detection of Dup/Del analysis is half that as the previously used code for BRCA1/2 Dup/del uncommon analysis.

21 Background: Oncology-related Procedures- Common Variants or Targeted Sequencing Procedures (81X08-81X11, 80X00) New Code Descriptor 81X08 EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit) (eg, diffuse large B-cell lymphoma) gene analysis, common variant(s) (eg, codon 646) 81X09 BTK (Bruton's tyrosine kinase) (eg, chronic lymphocytic leukemia) gene analysis, common variants (eg, C481S, C481R, C481F) 81X10 81X11 80X00 PLCG2 (phospholipase C gamma 2) (eg, chronic lymphocytic leukemia) gene analysis, common variants (eg, R665W, S707F, L845F) MYD88 (myeloid differentiation primary response 88) (eg, Waldenstrom s macroglobulinemia, lymphoplasmacytic leukemia) gene analysis, p.leu265pro (L265P) variant TERT (telomerase reverse transcriptase) (eg, thyroid carcinoma, glioblastoma multiforme) gene analysis, targeted sequence analysis (eg, promoter region)

22 Test Purpose and Method: Oncology-related Procedures- Common Variants or Targeted Sequencing Procedures (81X08-81X11, 80X00) Purpose: To detect common variant(s) in a gene or gene promoter region. Method: PCR amplification followed by a targeted genotyping method (e.g., Sanger Sequencing)

23 Crosswalk Recommendations: Oncology-related Procedures- Common Variants Or Targeted Sequencing Procedures (81X08-81X11, 80X00) New Code Gene Name Public Comment Rationale 81X08 81X09 EZH2 BTK BRAF (B-Raf proto-oncogene, serine/threonine kinase) (eg, colon cancer, melanoma), gene analysis, V600 variant(s) ($175.40) BRAF (B-Raf proto-oncogene, serine/threonine kinase) (eg, colon cancer, melanoma), gene analysis, V600 variant(s) ($175.40) Assessment of a single codon, hotspot variant. Similar methodologies are employed to detect variants at V600 in BRAF (81210) Assessment of a single codon, hotspot variant. Similar methodologies are employed to detect variants at V600 in BRAF (81210) 81X10 PLCG CYP2C19 (cytochrome P450, family 2, subfamily C, polypeptide 19) (eg, drug metabolism), gene analysis, common variants (eg, *2, *3, *4, *8, *17) ($291.36) Similar methodologies and resources are used in the assessment of 3 distant codons compared to 5 common variants in X11 MYD BRAF (B-Raf proto-oncogene, serine/threonine kinase) (eg, colon cancer, melanoma), gene analysis, V600 variant(s) ($175.40) Assessment of a single codon, hotspot variant. Similar methodologies are employed to detect variants at V600 in BRAF (81210) 80X00 TERT IDH2 (isocitrate dehydrogenase 2 [NADP+], mitochondrial) (eg, glioma), common variants (eg, R140W, R172M) ($295.79) Similar methodologies and resources are used to determine the genotype at two distant codons in IDH2.

24 Background and Test Purpose and Methods: Oncology-related Procedures- Full Gene Sequence Procedures (81X07) New Code Descriptor 81X07 EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit) (eg, myelodysplastic syndrome, myeloproliferative neoplasms) gene analysis, full gene sequence Test Purpose: 81X07: To detect variants (SNV and small indels) in the entire EZH2 gene in cancer or precancer Method: 81X07: PCR amplification follow by Sanger sequencing or next generation sequencing.

25 Crosswalk Recommendations: Oncology-related Procedures- Full Gene Sequence Procedures (81X07) New Code 81X07 EZH2 Gene Name Public Comment Rationale ASXL1 (additional sex combs like 1, transcriptional regulator) The methodology and amount of DNA (eg, myelodysplastic syndrome, myeloproliferative neoplasms, sequenced is comparable to the sequencing chronic myelomonocytic leukemia), gene analysis; full gene sequence of ASXL1, which is also relevant in ( $707.00) hematologic malignancy.

26 Background and Test Purpose and Methods: Genomic Sequencing Procedure 81X43 New Code Descriptor 81X43 Genetic testing for severe inherited conditions (eg, cystic fibrosis, Ashkenazi Jewish disorders [eg, Bloom syndrome, Canavan disease, Fanconi anemia type C, mucolipidosis type VI, Gaucher disease, Tay-Sachs disease], beta hemoglobinopathies, phenylketonuria, galactosemia), genomic sequence analysis panel, must include sequencing of at least 15 genes (eg, ACADM, ARSA, ASPA, ATP7B, BCKDHA, BCKDHB, BLM, CFTR, DHCR7, FANCC, G6PC, GAA, GALT, GBA, GBE1, HBB, HEXA, IKBKAP, MCOLN1, PAH) Test Purpose: To detect carrier status in diseases relevant to severe inherited disease. Method: Next generation sequencing

27 Crosswalk Recommendation: Genomic Sequencing Procedure 81X43 New Code 81X43 Short Descriptor Public Comment Rationale Genetic testing for severe inherited conditions Ashkenazi Jewish associated disorders (eg, Bloom syndrome, Canavan disease, cystic fibrosis, familial dysautonomia, Fanconi anemia group C, Gaucher disease, Tay-Sachs disease), genomic sequence analysis panel, must include sequencing of at least 9 genes, including ASPA, BLM, CFTR, FANCC, GBA, HEXA, IKBKAP, MCOLN1, and SMPD1 ($2,448,56) The methodologies and amount of resources required are similar for these clinically- similar codes.

28 Background and Test Purpose and Methods: Reconsidered Procedures (81334 and 81326) New Code Descriptor RUNX1 (runt related transcription factor 1) (eg, acute myeloid leukemia, familial platelet disorder with associated myeloid malignancy), gene analysis, targeted sequence analysis (eg, exons 3-8). PMP22 (peripheral myelin protein 22) (eg, Charcot-Marie-Tooth, hereditary neuropathy with liability to pressure palsies) gene analysis; known familial variant. Test Purpose: 81334: To detect somatic mutations in genes associated with the diagnosis or prognosis of certain hematologic malignancies : To detect known familial variants in a patient suspected of being affected by autosomal dominant Charcot-Marie-Tooth or a related neuropathy. Methods: 81334: PCR amplification followed by a genotyping method (i.e., sanger sequencing) 81326: For point mutations, PCR amplification and genotyping analysis is used. For del/dup analysis, a multiplex ligation dependent probe amplification (MLPA) is used.

29 Crosswalk Recommendations: Reconsidered Procedures (81334 and 81326) Code Gene Name Public Comment Rationale RUNX PMP HBA1/HBA2 (alpha globin 1 and alpha globin 2) (eg, alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis; full gene sequence ($600.00) BRCA1 (breast cancer 1) (eg, hereditary breast and ovarian cancer) gene analysis; known familial variant ($375.25) The test methods used for sequencing analysis and the amount of DNA sequenced are comparable to that for Similar methodologies and resources are used to detect known variants in BRCA which can be both point mutations or del/dups. Both conditions are autosomal dominant.